A rare case of straight-back syndrome causing airway obstruction

Background: Straight-back syndrome is a rare congenital condition involving the loss of the normal dorsal curvature of the upper thoracic spine. This leads to flattening of the upper thoracic cavity, resulting in compression of the underlying vasculature and airways. In this case report, we discuss the management of an 18-year-old male with straight-back syndrome who was referred to our interventional pulmonary clinic for further management of his stridor and apneic events. A trial of airway stenting was done which resolved the patient's respiratory symptoms. Definitive surgical correction was not applicable due to other significant medical conditions, but tracheostomy provided a sustainable alternative treatment. Tracheostomy tube placement and airway stenting are reasonable alternatives to surgery for patients who experience airway obstruction due to straight-back syndrome. Stent placement may also relieve respiratory symptoms but is associated with a higher rate of complications

Underutilization of Systemic Therapy in Patients With NSCLC Undergoing Pneumonectomy: A Missed Opportunity for Survival

Introduction: Recent trials have reported promising results with the addition of immunotherapy to chemotherapy for patients with locally advanced NSCLC, but in practice, the proportion of patients who receive systemic therapy (ST) has historically been low. Underutilization of ST may be particularly apparent in patients undergoing pneumonectomy, in whom the physiologic insult and surgical complications may preclude adjuvant therapy (ADJ). We, therefore, evaluated the use of ST for patients with NSCLC undergoing pneumonectomy. Methods: We queried the National Cancer Database, including all patients with NSCLC who underwent pneumonectomy between 2006 and 2018. Logistic regression was used to identify associations with ST and neo-ADJ (NEO). Overall survival was compared after propensity score matching (1:1) patients undergoing ST to those undergoing surgery alone using Kaplan-Meier and Cox regression methods. Results: A total of 2619 patients were identified. Among these, 12% received NEO, 43% received ADJ, and 45% surgery alone. Age younger than 65 years (adjusted odds ratio [aOR] = 1.53, 95% confidence interval; [CI]: 1.10–2.11), Asian ethnicity (aOR = 2.68, 95% CI: 1.37–5.23), treatment at a high-volume center (aOR = 1.39, 95% CI: 1.06–1.81), and private insurance (aOR = 1.42, 95% CI: 1.05–1.94) were associated with NEO, whereas age younger than 65 years (aOR = 1.95, 95% CI: 1.61–2.38), comorbidity index less than or equal to 1 (aOR = 1.66, 95% CI: 1.29–2.16), and private insurance (aOR = 1.47, 95% CI: 1.20–1.80) were associated with any ST. In the matched cohort, ST was associated with better survival than surgery (adjusted hazard ratio = 0.67, 95% CI: 0.58–0.78). Conclusions: A high proportion of patients who undergo pneumonectomy do not receive ST. Patient and socioeconomic factors are associated with the receipt of ST. Given its survival benefit, emphasis should be placed on multimodal treatment strategies, perhaps with greater consideration given to neoadjuvant approaches

Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (<b>2</b>), a full agonist of GPR40. Herein, we present further structure–activity relationships progressing from AM-1638 (<b>2</b>) to AM-6226 (<b>14</b>) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (<b>14</b>) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control

A Potent Class of GPR40 Full Agonists Engages the EnteroInsular Axis to Promote Glucose Control in Rodents

<div><p>Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9–39)NH₂.</p> </div

<i>In vitro</i> characterization of AM-1638 and AM-6226 and comparison to AMG 837.

<p>(A) Aequorin Ca²⁺ assay comparing AMG 837 to natural fatty acid ligands DHA, α-LNN and arachidonic acid. (B) Chemical structures of the key compounds synthesized during the medicinal chemistry effort that led to the discovery of AM-1638 and AM-6226. (C) Aequorin Ca²⁺ flux with key synthetic agonists and fatty acids. (D) Inositol phosphate assay with key synthetic agonists and fatty acids. (E–G) Plasmid titration experiments to examine agonist activity under conditions with reduced receptor levels, where either 5000 ng (E), 500 ng (F) or 50 ng (G) of GPR40 (FFAR1) expression plasmid was co-transfected with aequorin expression plasmids into CHO cells. (H) Competition binding experiment with ³H-AMG 837. (I) Competition binding experiment with ³H-AM-1638.</p

Specificity of AM-1638 to GPR40 (FFAR1) <i>in vivo</i> and effect of the GLP-1R antagonist GLP-1(9–39)NH₂.

<p>An OGTT was performed in (A) wild type or (B) GPR40 null mice following a single oral dose of AM-1638 or sitagliptin. Glucose was dosed 1-hr post drug treatment. (C) Glucose AUC during OGTT. (D) GLP-1 secretion following a single oral dose of AM-1638 in wild type or GPR40 null mice. AM-1638 (60 mg/kg) was tested in an IPGTT in the presence or absence of the GLP-1R antagonist GLP-1(9–39)NH₂ (300 µg/kg) as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046300#s4" target="_blank">Materials and Methods</a> section. (E) Plasma glucose levels (F) Glucose AUC and (G) plasma insulin levels at the indicated timepoints during the experiment. Statistical significance compared to vehicle treatment is denoted by *(p<0.05), **(p<0.01), ***(p<0.001) and ****(p<0.0001), as determined by one-way or two-way ANOVA, and are color-coded to the treatment in the figure legends.</p

Model depicting the dual mechanism-of-action of GPR40 (FFAR1) full agonists to lower blood glucose levels.

<p>GPR40 full agonists engage both the enteroendocrine axis as well as the pancreatic β-cell axis. These pathways both lead to augmentation of glucose stimulated insulin secretion on the pancreatic β-cell. Additionally, GLP-1 has multiple physiological and pharmacological roles, such as inhibition of glucagon secretion, that could further benefit type 2 diabetics. GPR40 partial agonists such as AMG 837 engage only the pancreatic pancreatic β-cell axis <i>in vivo</i>.</p

Activity of AM-1638 and AM-6226 in primary cells.

<p>(A) GSIS assay in mouse islets incubated with a dose response of compounds in the presence of 16.7 mM glucose. (B) Mouse islet perifusion assay. The glucose concentration was raised from 3 mM to 16.7 mM at t = 20 minutes and returned to 3 mM glucose at t = 30 minutes. 10 µM compound was perifused through the entire experiment. (C) GSIS assay with islets from wild type or GPR40 knock-out mice. (D) Inositol phosphate assay with dispersed human islet cells. (E) GSIS assay with human islets incubated with GPR40 agonists and 12.5 mM glucose. (F) GLP-1 secretion assay with fetal rat intestinal cells. (G) GIP-1 secretion assay with fetal rat intestinal cells. (H) Inositol phosphate accumulation assay using the mouse GLUTag enteroendocrine L-cell line. Statistical significance is denoted by *(p<0.05), **(p<0.01), ***(p<0.001) and ****(p<0.0001), as determined by one-way or two-way ANOVA, and are color-coded to treatment in the figure legends. For (A), (B), (F), (G), and (H) statistical comparisons were made to AMG 837 treatment. For (C) and (E) statistical comparisons were made to vehicle treatment.</p